From the perspective of cancer chemoprevention, an important strategy is to inhibit cell division and/or reduce the survival of cancer cells or to make the cells more sensitive to co-therapy. This goal can be achieved by reducing the level or activity of cell survival proteins. The polycomb group (PcG) genes encode an important group of cell survival proteins, which were originally discovered to enhance stem cell survival. These proteins act, via global epigenetic (chromatin modification) mechanisms, to suppress gene expression and enhance cell survival. They are key epigenetic controllers. Because they promote cell proliferation and survival and operate via an epigenetic mechanism, PcG proteins are regarded as having great potential as anti-cancer therapeutic targets. In spite of the potential importance of the PcG genes in enhancing cancer cell survival, the role of diet-derived chemopreventive agents in modulating their function has not been addressed. Bmi-1 is a polycomb protein that is expressed at high levels in some tumor types. Our preliminary studies show that Bmi-1 is markedly overexpressed in skin cancer cells and tumors, and that targeted overexpression of Bmi-1 enhances skin cancer cell survival. In addition, our studies show that the bioactive polyphenol present in green tea, (-)-epigallocatechin-3-gallate (EGCG), reduces Bmi-1 level and that this reduction is associated with reduced skin cancer cell proliferation and survival. These findings suggest that chemopreventive agents may act to reduce skin cancer by reducing Bmi-1 level and activity. The idea that chemopreventive agents may act by interfering with PcG gene- dependent epigenetic regulatory mechanisms has not been widely considered or studied. The major goal of this proposal is to understand how EGCG acts to regulate Bmi-1 level and activity in skin cancer. The studies outlined in Specific Aim 1 are designed to determine the mechanism(s) whereby EGCG reduces Bmi-1 level and activity. The experiments outlined in Specific Aim 2 are designed to understanding how the EGCG-dependent reduction in Bmi-1 level results in reduced skin cancer cell survival. Specific Aim 3 focuses on the contribution of other PcG gene products that are part of the Bmi-1 multiprotein complex, and Specific Aim 4 examines the in vivo role of Bmi-1 using an epidermis-targeted Bmi-1 overexpression model to study UVB-dependent skin carcinogenesis. PUBLIC HEALTH RELEVANCE The polycomb (PcG) proteins act via epigenetic (chromatin modification) mechanisms to enhance cancer cell survival. Because of this property, PcG proteins are regarded as having great potential as anti-cancer therapy targets. Green tea polyphenols are important diet-derived cancer preventive agents that prevent UV light-dependent skin cancer. Our studies show that an active agent in green tea reduces polycomb gene expression in skin cancer cells making them more susceptible to cell death. Our goal is to determine whether suppression of the level and function of the Bmi-1 PcG protein is a mechanism whereby green tea polyphenols inhibit the development of ultraviolet light-dependent skin cancer. These studies are regarded as innovative because the impact of chemopreventive agents on this important type of epigenetic regulation has not been previously considered for study.